Phase II Trial of Dabrafenib Plus Trametinib in Relapsed/Refractory BRAF V600-Mutant Pediatric High-Grade Glioma

PURPOSE: BRAF V600 mutation is detected in 5%-10% of pediatric high-grade gliomas (pHGGs), and effective treatments are limited. In previous trials, dabrafenib as monotherapy or in combination with trametinib demonstrated activity in children and adults with relapsed/refractory BRAF V600-mutant HGG. METHODS: This phase II study evaluated dabrafenib plus trametinib in patients with relapsed/refractory BRAF V600-mutant pHGG. The primary objective was overall response rate (ORR) by independent review by Response Assessment in Neuro-Oncology criteria. Secondary objectives included ORR by investigator determination, duration of response (DOR), progression-free survival, overall survival (OS), and safety. RESULTS: A total of 41 pediatric patients with previously treated BRAF V600-mutant HGG were enrolled. At primary analysis, median follow-up was 25.1 months, and 51% of patients remained on treatment. Sixteen of 20 discontinuations were due to progressive disease in this relapsed/refractory pHGG population. Independently assessed ORR was 56% (95% CI, 40 to 72). Median DOR was 22.2 months (95% CI, 7.6 months to not reached [NR]). Fourteen deaths were reported. Median OS was 32.8 months (95% CI, 19.2 months to NR). The most common all-cause adverse events (AEs) were pyrexia (51%), headache (34%), and dry skin (32%). Two patients (5%) had AEs (both rash) leading to discontinuation. CONCLUSION: In relapsed/refractory BRAF V600-mutant pHGG, dabrafenib plus trametinib improved ORR versus previous trials of chemotherapy in molecularly unselected patients with pHGG and was associated with durable responses and encouraging survival. These findings suggest that dabrafenib plus trametinib is a promising targeted therapy option for children and adolescents with relapsed/refractory BRAF V600-mutant HGG

Alterations in ALK/ROS1/NTRK/MET drive a group of infantile hemispheric gliomas

© The Author(s) 2019. Open Access. This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons license and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/.Infant gliomas have paradoxical clinical behavior compared to those in children and adults: low-grade tumors have a higher mortality rate, while high-grade tumors have a better outcome. However, we have little understanding of their biology and therefore cannot explain this behavior nor what constitutes optimal clinical management. Here we report a comprehensive genetic analysis of an international cohort of clinically annotated infant gliomas, revealing 3 clinical subgroups. Group 1 tumors arise in the cerebral hemispheres and harbor alterations in the receptor tyrosine kinases ALK, ROS1, NTRK and MET. These are typically single-events and confer an intermediate outcome. Groups 2 and 3 gliomas harbor RAS/MAPK pathway mutations and arise in the hemispheres and midline, respectively. Group 2 tumors have excellent long-term survival, while group 3 tumors progress rapidly and do not respond well to chemoradiation. We conclude that infant gliomas comprise 3 subgroups, justifying the need for specialized therapeutic strategies.info:eu-repo/semantics/publishedVersio

The whole blood transcriptional regulation landscape in 465 COVID-19 infected samples from Japan COVID-19 Task Force

「コロナ制圧タスクフォース」COVID-19患者由来の血液細胞における遺伝子発現の網羅的解析 --重症度に応じた遺伝子発現の変化には、ヒトゲノム配列の個人差が影響する--. 京都大学プレスリリース. 2022-08-23.Coronavirus disease 2019 (COVID-19) is a recently-emerged infectious disease that has caused millions of deaths, where comprehensive understanding of disease mechanisms is still unestablished. In particular, studies of gene expression dynamics and regulation landscape in COVID-19 infected individuals are limited. Here, we report on a thorough analysis of whole blood RNA-seq data from 465 genotyped samples from the Japan COVID-19 Task Force, including 359 severe and 106 non-severe COVID-19 cases. We discover 1169 putative causal expression quantitative trait loci (eQTLs) including 34 possible colocalizations with biobank fine-mapping results of hematopoietic traits in a Japanese population, 1549 putative causal splice QTLs (sQTLs; e.g. two independent sQTLs at TOR1AIP1), as well as biologically interpretable trans-eQTL examples (e.g., REST and STING1), all fine-mapped at single variant resolution. We perform differential gene expression analysis to elucidate 198 genes with increased expression in severe COVID-19 cases and enriched for innate immune-related functions. Finally, we evaluate the limited but non-zero effect of COVID-19 phenotype on eQTL discovery, and highlight the presence of COVID-19 severity-interaction eQTLs (ieQTLs; e.g., CLEC4C and MYBL2). Our study provides a comprehensive catalog of whole blood regulatory variants in Japanese, as well as a reference for transcriptional landscapes in response to COVID-19 infection

DOCK2 is involved in the host genetics and biology of severe COVID-19

「コロナ制圧タスクフォース」COVID-19疾患感受性遺伝子DOCK2の重症化機序を解明 --アジア最大のバイオレポジトリーでCOVID-19の治療標的を発見--. 京都大学プレスリリース. 2022-08-10.Identifying the host genetic factors underlying severe COVID-19 is an emerging challenge. Here we conducted a genome-wide association study (GWAS) involving 2, 393 cases of COVID-19 in a cohort of Japanese individuals collected during the initial waves of the pandemic, with 3, 289 unaffected controls. We identified a variant on chromosome 5 at 5q35 (rs60200309-A), close to the dedicator of cytokinesis 2 gene (DOCK2), which was associated with severe COVID-19 in patients less than 65 years of age. This risk allele was prevalent in East Asian individuals but rare in Europeans, highlighting the value of genome-wide association studies in non-European populations. RNA-sequencing analysis of 473 bulk peripheral blood samples identified decreased expression of DOCK2 associated with the risk allele in these younger patients. DOCK2 expression was suppressed in patients with severe cases of COVID-19. Single-cell RNA-sequencing analysis (n = 61 individuals) identified cell-type-specific downregulation of DOCK2 and a COVID-19-specific decreasing effect of the risk allele on DOCK2 expression in non-classical monocytes. Immunohistochemistry of lung specimens from patients with severe COVID-19 pneumonia showed suppressed DOCK2 expression. Moreover, inhibition of DOCK2 function with CPYPP increased the severity of pneumonia in a Syrian hamster model of SARS-CoV-2 infection, characterized by weight loss, lung oedema, enhanced viral loads, impaired macrophage recruitment and dysregulated type I interferon responses. We conclude that DOCK2 has an important role in the host immune response to SARS-CoV-2 infection and the development of severe COVID-19, and could be further explored as a potential biomarker and/or therapeutic target

Reinforcement Learning for Multi-Agent Systems with Temporal Logic Specifications

In a multi-agent system, it is important to consider a design method of cooperative actions in order to achieve a common goal. In this paper, we propose two novel multi-agent reinforcement learning methods, where the control specification is described by linear temporal logic formulas, which represent a common goal. First, we propose a simple solution method, which is directly extended from the single-agent case. In this method, there are some technical issues caused by the increase in the number of agents. Next, to overcome these technical issues, we propose a new method in which an aggregator is introduced. Finally, these two methods are compared by numerical simulations, with a surveillance problem as an example

Tumor-Treating Fields Therapy for Pediatric Brain Tumors

Tumor-treating fields (TTFields) are alternating electric fields applied continuously to the brain by attaching two-pair arrays on the scalp. Although TTFields therapy has demonstrated efficacy against supratentorial glioblastoma (GBM) in adults, its safety and efficacy in children have not been confirmed. Despite differences in the genetic etiology of the adult and pediatric forms of GBM, both have certain clinical behaviors in common, allowing us to test TTFields therapy in pediatric GBM. Recently, several, pediatric case-series using TTFields therapy have been published, and a few, prospective, pediatric studies are ongoing. Because GBMs are extremely rare in pediatric patients, where they comprise a wide variety of genetic subtypes, these pediatric studies are feasibility studies targeting various types of malignant brain tumor. Although they are important for confirming the safety and feasibility of TTFields therapy in the pediatric population, confirming its efficacy against each type of pediatric brain tumor, including the GBM, is difficult. Our clinical research team, therefore, planned an investigator-initiated clinical trial targeting pediatric supratentorial GBMs (as in adults) with the aim of expanding regulatory approval of TTFields therapy for pediatric GBM treatment based on safety and exploratory efficacy data in combination with the accumulated evidence on adult GBMs